Spatial and Topological Organization of DNA Chains Induced by Gene Co-localization

Abstract

Transcriptional activity has been shown to relate to the organization of chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In particular, highly transcribed genes, RNA polymerases and transcription factors gather into discrete spatial foci called transcription factories. However, the mechanisms underlying the formation of these foci and the resulting topological order of the chromosome remain to be elucidated. Here we consider a thermodynamic framework based on a worm-like chain model of chromosomes where sparse designated sites along the DNA are able to interact whenever they are spatially close by. This is motivated by recurrent evidence that there exist physical interactions between genes that operate together. Three important results come out of this simple framework. First, the resulting formation of transcription foci can be viewed as a micro-phase separation of the interacting sites from the rest of the DNA. In this respect, a thermodynamic analysis suggests transcription factors to be appropriate candidates for mediating the physical interactions between genes. Next, numerical simulations of the polymer reveal a rich variety of phases that are associated with different topological orderings, each providing a way to increase the local concentrations of the interacting sites. Finally, the numerical results show that both one-dimensional clustering and periodic location of the binding sites along the DNA, which have been observed in several organisms, make the spatial co-localization of multiple families of genes particularly efficient.

On the demultiplexing of chromosome capture conformation data

“…Next, both attractive and repulsing interactions appear to be required to recapitulate experimental contact maps. Large attracting energies are compatible with a bridging mechanism that is induced by large protein complexes [49], which is consistent with the CTCF enrichment of the strongest interacting sites [24]; non-specific (weak) interacting energies may instead indicate a global interaction network between domains with similar epigenomic profiles [44]. The rationale for repulsive interactions is less clear.…”

Non-specific (entropic) forces as major determinants of the structure of mammalian chromosomes

“…b Two preferred conformations of tubes in which inter-segment interactions are stronger than segment:solvent ones; maximizing the buried surface area of the tube drives compaction into single or double helices. This kind of force transcends chemical detail, and acts over many scales (e.g., it probably underlies the formation of α-helices in proteins, double helices in DNA, and the coiling of chromatin fibres in vitro) form (Marenduzzo et al 2006a;Junier et al 2010). The attraction can also bring together large heterochromatic clumps-which might be nucleolar organizing regions (NORs) or centromeres-into nucleoli or chromocentres (Fig.…”

Transcriptional regulatory network shapes the genome structure ofSaccharomyces cerevisiae

“…[10][11][12] One of ideas is the transcription induced gene co-localization. 11,13 Transcription factories are discrete structures within the cell nucleus enriched with a transcription apparatus, like polymerases, TFs and nascent RNA splicing apparatus. 14 They are thought to play an architectural role in genome organization by tying up the actively expressed genes.…”

“…14 They are thought to play an architectural role in genome organization by tying up the actively expressed genes. 11,13,15 Since the number of synchronously expressed genes is far beyond that of transcription factories, multiple activated genes have to colocalize at the same expression foci. Genes occupying the same transcription factories might come from distant parts of the same chromosome or even from different chromosomes, which will induce the intra-chromosomal loops or inter-chromosomal bridges.…”

“…Two models based on the transcription induced gene co-localization were proposed by Junier et al 11 and by Dorier et al, 30 respectively. These models, however, are not realistic enough to explain what we are learning from nuclei structures 27,28 and gene expression phenomena.…”